Abstract:

Copper ions are essential for almost all living beings and tight control of copper binding and coordination is important as copper is potentially dangerous, often via its high capacity to activate dioxygen and hence catalyze the production of reactive oxygen species. Several diseases are linked more or less to a dyshomeostasis of copper such as Wilson’s and Menkes genetic disorders, Alzheimer’s disease, Parkinson’s, cancer etc... Thus, interfering in copper metabolism via small ligands is a widely investigated therapeutic approach and, in some cases like Wilson disease, routinely used in clinics.

Inorganic copper-complexes can be applied or formed in situ when a chelator is able to bind endogenous Cu. They can act either by supplying, sequestering or transporting copper, or by catalyzing targeted chemical reactions often via O₂ activation. The latter case is thought to be of high importance in development of anti-cancer drugs or for antimicrobials. The canonical example is targeting DNA cleavage by copper-complexes via O₂ activation.

During the last years we worked on the Cu chemistry of several biological relevant peptides, chelators and complexes. This includes the amyloid-β peptide related to Alzheimer’s disease (1,2), several thiosemicarbazones (3) and lately also other classical ligand types (phenantroline, dithiocarbamate, bleomycin, bipyridine etc.) (4). We could provide fundamental insights linking high redox-activity and ROS production of Cu-complexes on one side and stability against intracellular thiols from glutathione and metallothioneins on the other side. The results indicate the extremely difficult task to design small redox active copper-complexes with cytosolic or nuclear activity and sheds light on the mechanism of Cu-complexes and –chelators in the cell. Moreover, this underlines the importance to consider cellular thiols for the fate of metal-complexes in general.

1) Santoro A, et al.: Chem. Comm., 54, 12634 - 12637 (2018)
2) Santoro A, et al. Chem. Comm., 54, 11945 - 11948 (2018)
3) Santoro A, et al.: Metallomics, 11, 994-1004 (2019)
4) Santoro A. et al. Angew. Chem. Int. Ed. provisionally accepted

• Prof. Peter Faller, Biometals and Biology Chemistry, Institut de Chimie (CNRS UMR 7177), University of Strasbourg, 4 rue B. Pascal, 67081 Strasbourg, France.
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